Pyrazole compositions useful as inhibitors of ERK

ABSTRACT

Described herein are compounds that are useful as protein kinase inhibitors having the formula:                    
     where R 1-4 , Q, and T are described in the specification. The compounds are useful for treating disease states in mammals that are alleviated by a protein kinase inhibitor, particularly diseases such as cancer, inflammatory disorders, restenosis, and cardiovascular disease.

This application claims the priority to co-pending International PatentApplication PCT/US03911, filed Feb. 5, 2001, which claims priority ofUnited States Provisional Application serial No. 60/180,506 filed Feb.5, 2000; U.S. Provisional Application serial No. 60/242,935 filed Oct.24, 2000; and U.S. Provisional Application serial No. 60/191,956 filedMar. 24, 2000. The entire of which is herein incorporated by reference.

FIELD OF THE INVENTION

The present invention is in the field of medicinal chemistry and relatesto pyrazole compounds that are protein kinase inhibitors, especiallyinhibitors of ERK, compositions containing such compounds and methods ofuse. The compounds are useful for treating cancer and other diseasestates that are alleviated by protein kinase inhibitors.

BACKGROUND OF THE INVENTION

Mammalian mitogen-activated protein (MAP)1 kinases are serine/threoninekinases that mediate intracellular signal transduction pathways (Cobband Goldsmith, 1995, J Biol. Chem., 270, 14843; Davis, 1995, Mol.Reprod. Dev. 42, 459). Members of the MAP kinase family share sequencesimilarity and conserved structural domains, and include the ERK(extracellular signal regulated kinase), JNK (Jun N-terminal kinase),and p38 kinases. JNKs and p38 kinases are activated in response to thepro-inflammatory cytokines TNF-alpha and interleukin-1, and by cellularstress such as heat shock, hyperosmolarity, ultraviolet radiation,lipopolysaccharides and inhibitors of protein synthesis (Derijard etal., 1994, Cell 76, 1025; Han et al., 1994, Science 265, 808; Raingeaudet al., 1995, J Biol. Chem. 270, 7420; Shapiro and Dinarello, 1995,Proc. Natl. Acad. Sci. USA 92, 12230). In contrast, ERKs are activatedby mitogens and growth factors (Bokemeyer et al. 1996, Kidney Int. 49,1187).

ERK2 is a widely distributed protein kinase that achieves maximumactivity when both Thr183 and Tyr185 are phosphorylated by the upstreamMAP kinase kinase, MEK1 (Anderson et al., 1990, Nature 343, 651; Crewset al., 1992, Science 258, 478). Upon activation, ERK2 phosphorylatesmany regulatory proteins, including the protein kinases Rsk90 (Bjorbaeket al., 1995, J. Biol. Chem. 270, 18848) and MAPKAP2 (Rouse et al.,1994, Cell 78, 1027), and transcription factors such as ATF2 (Raingeaudet al., 1996, Mol. Cell Biol. 16, 1247), Elk-1 (Raingeaud et al. 1996),c-Fos (Chen et al., 1993 Proc. Natl. Acad. Sci. USA 90, 10952), andc-Myc (Oliver et al., 1995, Proc. Soc. Exp. Biol. Med. 210, 162). ERK2is also a downstream target of the Ras/Raf dependent pathways (Moodie etal., 1993, Science 260, 1658) and may help relay the signals from thesepotentially oncogenic proteins. ERK2 has been shown to play a role inthe negative growth control of breast cancer cells (Frey and Mulder,1997, Cancer Res. 57, 628) and hyperexpression of ERK2 in human breastcancer has been reported (Sivaraman et al., 1997, J Clin. Invest. 99,1478). Activated ERK2 has also been implicated in the proliferation ofendothelin-stimulated airway smooth muscle cells, suggesting a role forthis kinase in asthma (Whelchel et al., 1997, Am. J. Respir. Cell Mol.Biol. 16, 589).

The JNK family of (MAP)1 kinases have been implicated in having a rolein mediating cellular response to a variety of disorders includingcancer (Oncogene 1996, 13, 135-42), hepatic disorders (Hepatology 1998,28,1022-30), cardiovascular disease (Circ. Res. 1998, 83, 167-78;Circulation 1998, 97:1731-7; J. Biol. Chem. 1997, 272, 28050-6; Circ.Res. 1996, 79, 162-73; Circ. Res. 1996, 78, 947-53; J. Clin. Invest.1996, 97, 508-14), and immunological disorders (J. Immunol. 1999, 162,3176-87; Eur. J. Immunol. 1998, 28, 3867-77; J. Exp. Med. 1997, 186,941-53; Eur. J. Immunol. 1996, 26, 989-94, among others).

Aurora2 is a serine/threonine protein kinase that has been implicated inhuman cancer, such as colon, breast and other solid tumors. This kinaseis believed to be involved in protein phosphorylation events thatregulate the cell cycle. Specifically, aurora2 may play a role incontrolling the accurate segregation of chromosomes during mitosis.Misregulation of the cell cycle can lead to cellular proliferation andother abnormalities. In human colon cancer tissue, the aurora2 proteinhas been found to be overexpressed. See Bischoff et al., EMBO J., 1998,17, 3052-3065; Schumacher et al., J. Cell Biol., 1998, 143, 1635-1646;Kimura et al., J. Biol. Chem., 1997, 272, 13766-13771.

Glycogen synthase kinase-3 (GSK-3) is a serine/threonine protein kinasecomprised of α and β isoforms that are each encoded by distinct genes[Coghlan et al., Chemistry & Biology, 7, 793-803 (2000); Kimand Kimmel,Curr. Opinion Genetics Dev., 10, 508-514 (2000)]. GSK-3 has beenimplicated in various diseases including diabetes, Alzheimer's disease,CNS disorders such as manic depressive disorder and neurodegenerativediseases, and cardiomyocete hypertrophy [WO 99/65897; WO 00/38675; andHaq et al., J. Cell Biol. (2000) 151, 117]. These diseases may be causedby, or result in, the abnormal operation of certain cell signalingpathways in which GSK-3 plays a role.

KDR is a tyrosine kinase receptor that also binds VEGF (vascularendothelial growth factor) (Neufeld et al., 1999, FASEB J., 13, 9). Thebinding of VEGF to the KDR receptor leads to angiogenesis, which is thesprouting of capillaries from preexisting blood vessels. High levels ofVEGF are found in various cancers causing tumor angiogenesis andpermitting the rapid growth of cancerous cells. Therefore, suppressingVEGF activity is a way to inhibit tumor growth, and it has been shownthat this can be achieved by inhibiting KDR receptor tyrosine kinase.

AKT, also known as protein kinase B, is a serine/threonine kinase thatplays a central role in promoting the survival of a wide range of celltypes [Khwaja, A., Nature, pp. 33-34 (1990)]. It has been shown by Zang,et al, that human ovarian cancer cells display elevated levels of AKT-1and AKT-2. Inhibition of AKT induces apoptosis of these human ovariancancer cells which demonstrates that AKT may be an important target forovarian cancer treatment [Zang, Q. Y., et al, Oncogene, 19 (2000)] andother proliferative disorders. The AKT pathway has also been implicatedin motoneuronal survival and nerve regeneration [Kazuhiko, N., et al,The Journal of Neuroscience, 20 (2000)].

There is a high unmet medical need to develop protein kinase inhibitors,especially ERK inhibitors, that are useful in treating the variousconditions associated with ERK activation, especially considering thecurrently available, relatively inadequate treatment options for themajority of these conditions.

Accordingly, there is still a great need to develop potent inhibitors ofprotein kinase, including ERK inhibitors, that are useful in treatingvarious conditions associated with protein kinase activation.

DESCRIPTION OF THE INVENTION

It has now been found that compounds of this invention and compositionsthereof are effective as protein kinase inhibitors, especially asinhibitors of ERK. These compounds have the general formula I:

or a pharmaceutically acceptable derivative thereof, wherein:

R¹ is selected from R, halogen, N(R⁸)₂, OR, NRCOR, NRCON(R⁸)₂, CON(R⁸)₂,SO₂R, NRSO₂R, or SO₂N(R⁸)₂;

T is selected from a valence bond or a linker group;

each R is independently selected from hydrogen or an optionallysubstituted aliphatic group having one to six carbons;

R² is selected from hydrogen, CN, halogen, aryl, aralkyl, heteroaryl,heterocyclyl, an optionally substituted acyclic aliphatic chain grouphaving one to six carbons, or an optionally substituted cyclic aliphaticgroup having four to ten carbons;

R³ is selected from R, OH, OR, N(R⁸)₂, halogen, or CN;

Q is a valence bond, J, or an optionally substituted C₁₋₆ alkylidenechain wherein up to two nonadjacent carbons of the alkylidene chain areeach optionally and independently replaced by J;

J is selected from —C(═O)—, —CO₂—, —C(O)C(O)—, —NRCONR⁸—, —N(R)N(R⁸)—,—C(═O)NR⁸—, —NRC(═O)—, —O—, —S—, —SO—, —SO₂—, —N(R)O—, —ON(R⁸)—,—OC(═O)N(R⁸)—, —N(R)COO—, —SO₂N(R⁸)—, —N(R)SO₂—, or —N(R⁸)—;

R⁴ is selected from —R⁸, —R⁵, —NH₂, —NHR⁵, —N(R⁵)₂, or —NR⁵(CH₂)_(y)N(R⁵)₂;

each R⁵ is independently selected from R⁶, R⁷, —(CH₂)_(y)CH(R⁶)(R⁷),—(CH₂)_(y)R⁶, —(CH₂)_(y)CH(R⁶)₂, —(CH₂)_(y)CH(R⁷)₂, or —(CH₂)_(y)R⁷;

y is 0-6;

each R⁶ is an optionally substituted group independently selected froman aliphatic, aryl, aralkyl, aralkoxy, heteroaryl, heteroarylalkyl,heteroarylalkoxy, heterocyclyl, heterocyclylalkyl, orheterocyclylalkoxy, group;

each R⁷ is independently selected from an optionally substitutedhydroxyalkyl, alkoxyalkyl, aryloxyalkyl, or alkoxycarbonyl; and

each R⁸ is independently selected from R, or two R⁸ on the same nitrogentaken together with the nitrogen optionally form a four to eightmembered, saturated or unsaturated heterocyclic ring having one to threeheteroatoms.

As used herein, the following definitions shall apply unless otherwiseindicated. Also, combinations of substituents or variables arepermissible only if such combinations result in stable compounds.

The term “aliphatic” as used herein means straight chained, branched orcyclic C₁-C₁₂ hydrocarbons which are completely saturated or whichcontain one or more units of unsaturation. For example, suitablealiphatic groups include substituted or unsubstituted linear, branchedor cyclic alkyl, alkenyl, alkynyl groups and hybrids thereof such as(cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl. The term“alkyl” and “alkoxy” used alone or as part of a larger moiety refers toboth straight and branched chains containing one to twelve carbon atoms.The terms “alkenyl” and “alkynyl” used alone or as part of a largermoiety shall include both straight and branched chains containing two totwelve carbon atoms. The terms “haloalkyl”, “haloalkenyl” and“haloalkoxy” means alkyl, alkenyl or alkoxy, as the case may be,substituted with one or more halogen atoms. The term “halogen” means F,Cl, Br, or I. The term “heteroatom” means N, O, or S and shall includeany oxidized form of nitrogen and sulfur, and the quaternized form ofany basic nitrogen.

The term “aryl”, used alone or as part of a larger moiety as in“aralkyl”, refers to aromatic ring groups having five to fourteenmembers, such as phenyl, benzyl, 1-naphthyl, 2-naphthyl, 1-anthracyl and2-anthracyl, and heterocyclic aromatic groups or heteroaryl groups suchas 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl,5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxadiazolyl,5-oxadiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-pyrrolyl,3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl,5-pyrimidyl, 3-pyridazinyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl,5-tetrazolyl, 2-triazolyl, 5-triazolyl, 2-thienyl, or 3-thienyl. Theterm “aryl ring” also refers to rings that are optionally substituted.

Aryl groups also include fused polycyclic aromatic ring systems in whicha carbocyclic aromatic ring or heteroaryl ring is fused to one or moreother rings. Examples include tetrahydronaphthyl, benzimidazolyl,benzothienyl, benzofuranyl, indolyl, quinolinyl, benzothiazolyl,benzooxazolyl, benzimidazolyl, isoquinolinyl, isoindolyl, acridinyl,benzoisoxazolyl, and the like. Also included within the scope of theterm “aryl”, as it is used herein, is a group in which one or morecarbocyclic aromatic rings and/or heteroaryl rings are fused to acycloalkyl or non-aromatic heterocyclic ring, for example, indanyl ortetrahydrobenzopyranyl.

Non-aromatic heterocyclic rings are non-aromatic carbocyclic rings inwhich one or more ring carbons are replaced by a heteroatom such asnitrogen, oxygen or sulfur in the ring. The ring can be five, six, sevenor eight-membered and/or fused to another ring, such as a cycloalkyl oraromatic ring. Examples include 3-1H-benzimidazol-2-one,3-(1-alkyl)-benzimidazol-2-one, 2-tetrahydrofuranyl,3-tetrahydrofuranyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl,2-morpholino, 3-morpholino, 4-morpholino, 2-thiomorpholino,3-thiomorpholino, 4-thiomorpholino, 1-pyrrolidinyl, 2-pyrrolidinyl,3-pyrrolidinyl, 1-piperazinyl, 2-piperazinyl, 1-piperidinyl,2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 4-thiazolidinyl,diazolonyl, N-substituted diazolonyl, 1-phthalimidinyl, benzoxane,benzotriazol-1-yl, benzopyrrolidine, benzopiperidine, benzoxolane,benzothiolane, and benzothiane. The term “heterocyclic ring”, whethersaturated or unsaturated, also refers to rings that are optionallysubstituted.

An aryl group (carbocyclic and heterocyclic) or an aralkyl group, suchas benzyl or phenethyl, may contain one or more substituents. Examplesof suitable substituents on the unsaturated carbon atom of an aryl groupinclude a halogen, —R, —OR, —SR, protected OH (such as acyloxy), phenyl(Ph), substituted Ph, —OPh, substituted —OPh, —NO₂, —CN, —N(R)₂,—NRN(R)₂, —NRCON(R)₂, —NRCOR, —NRCO₂(aliphatic), —CO₂R, —COR,—C(O)C(O)R, —CON(R)₂, —CONRN(R)₂, —S(O)₂R, —SON(R)₂, —S(O) (aliphatic),—SO₂N(R)₂, or —NRS(O)₂R, where each R is independently selected fromhydrogen, an aliphatic group or a substituted aliphatic group.

An aliphatic group or a non-aromatic heterocyclic ring may contain oneor more substituents. Examples of suitable substituents on the saturatedcarbon of an aliphatic group or of a non-aromatic heterocyclic ringinclude those listed above for the unsaturated carbon as well as thefollowing: ═O, ═S, ═NNHR, ═NNR₂, ═N—, OR, ═NNHCOR, ═NNHCO₂ (aliphatic),═NNHSO₂ (aliphatic), or ═NR, where each R is independently selected fromhydrogen, an aliphatic group or a substituted aliphatic group.

The term “alkylidene chain” refers to an optionally substituted,straight or branched, carbon chain that may be fully saturated or haveone or more units of unsaturation. The optional substituents are asdescribed above for an aliphatic group. Optional substituents of theC₁₋₆ alkylidine chain of Q include those described above for analiphatic group.

The term “linker group” means an organic moiety that connects two partsof a compound. Linkers are typically comprised of an atom such as oxygenor sulfur, a unit such as —NH— or —CH₂—, or a chain of atoms, such as analkylidene chain. The molecular mass of a linker is typically in therange of about 14 to 200. Examples of linkers include a saturated orunsaturated C₁₋₆ alkylidene chain which is optionally substituted, andwherein up to two saturated carbons of the chain are optionally replacedby —C(═O)—, —CONH—, CONHNH—, —CO₂—, —NHCO₂—, —O—, —NHCONH—, —OC(═O)—,—OC(═O)NH—, —NHNH—, —NHCO—, —O—, —S—, —SO—, —SO₂—, —NH—, —SO₂NH—, orNHSO₂—.

It will be apparent to one skilled in the art that certain compounds ofthis invention may exist in tautomeric forms, all such tautomeric formsof the compounds being within the scope of the invention.

Unless otherwise stated, structures depicted herein are also meant toinclude all stereochemical forms of the structure; i.e., the R and Sconfigurations for each asymmetric center. Therefore, singlestereochemical isomers as well as enantiomeric and diastereomericmixtures of the present compounds are within the scope of the invention.Unless otherwise stated, structures depicted herein are also meant toinclude compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of a hydrogen by a deuterium ortritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbonare within the scope of this invention.

One embodiment of this invention relates to compounds of formula II:

wherein R¹, R², R³, R⁴, T, and Q are as described above.

A preferred embodiment of this invention relates to compounds having theformula:

wherein T, R², and R⁴ are as described above and R¹ and R³ are eachhydrogen.

Preferred compounds include those having one or more, and mostpreferably all, of the following features: (a) Q is —CO—, —CO₂—, or—CONH—; (b) T is a valence bond; (c) R¹ is hydrogen or NHR; (d) R² is anoptionally substituted aryl ring, more preferably an optionallysubstituted phenyl ring; (c) R³ is hydrogen; (e) R⁴ is selected from R⁵,—NHR⁵, —N(R⁵)₂, —NR⁵R⁶, —NHCHR⁵R⁶, or —NHCH₂R⁵; and/or (f) R⁵ is anoptionally substituted group selected from aryl, aralkyl, heteroaryl,heteroarylalkyl, heterocyclyl, heterocyclylalkyl group, (CH₂)_(y)R⁶,(CH₂)_(y)R⁷ or (CH₂)_(y)CH(R⁶)(R⁷) .

Examples of substitutions of the R² phenyl group include halo, nitro,alkoxy, and amino.

When R⁴ is R⁵, examples of preferred R⁵ groups include pyrrolidin-1-yl,morpholin-1-yl, piperidin-1-yl, and piperazin-1-yl wherein each group isoptionally substituted. When R⁴ is —NHR⁵ or —N(R⁵)₂, preferred R⁵ groupsfurther include (CH₂)_(y)R⁶, (CH₂)_(y)R⁷, and (CH₂)_(y)CH(R⁶)(R⁷).Examples of preferred R⁶ and R⁷ include pyridin-3-yl, pyridin-4-yl,imidazolyl, furan-2-yl, tetrahydrofuran-2-yl, cyclohexyl, phenyl,—CH₂OH, —(CH₂)₂OH, and isopropyl, wherein each group is optionallysubstituted.

Exemplary structures of formula II, wherein R¹ and R³ are each H, areset forth in Table 1 below.

TABLE 1 Compounds II II

No. T—R² Q—R⁴ II-1 phenyl CON(Me)₂ II-2 phenyl CO₂Et II-3 3-NO₂-phenylCONHNH₂ II-4 phenyl CO(pyrrolidin-1-yl) II-5 phenyl CONHCH₂(Ph) II-63-NO₂-phenyl CO₂Et II-7 4-Cl-phenyl CO₂Et II-8 4-OMe-phenyl CO₂Et II-93-NH₂-phenyl CO₂Et II-10 3-OMe-phenyl CO₂Et II-11 4-F-phenyl CO₂Et II-124-NO₂-phenyl CO₂Et II-13 3-Cl-phenyl CO₂Et II-14 3-F-phenyl CO₂Et II-15phenyl CO₂H II-16 4-NH₂-phenyl CO₂Et II-17 phenyl CONHCH₂CH₂N(Me)₂ II-18phenyl CONHCH₂(pyridin-3-yl) II-19 phenyl CO(morpholin-1-yl) II-20phenyl CONH(isopropyl) II-21 phenyl CO(4-Me-piperazin-1-yl) II-22 phenylCONHCH₂(furan-2-yl) II-23 3-OMe-phenyl CONMe₂ II-24 3-OMe-phenylCO(pyrrolidin-1-yl) II-25 3-OMe-phenyl CONHCH₂CH₂N(Me)₂ II-263-OMe-phenyl CONHCH₂(pyridin-3-yl) II-27 3-OMe-phenyl CO(morpholin-1-yl)II-28 3-OMe-phenyl CONH(isopropyl) II-29 3-OMe-phenylCO(4-Me-piperazin-1-yl) II-30 3-OMe-phenyl CONHCH₂(furan-2-yl) II-314-NH₂-phenyl CO₂Et II-32 H CONMe₂ II-33 H CO(pyrrolidin-1-yl) II-343-(AcNH)-phenyl CO₂Et II-35 4-(AcNH)-phenyl CO₂Et II-36 3-(AcNH)-phenylCO₂Et II-37 4-(AcNH)-phenyl CO₂Et II-38 3-Cl-phenyl CON(H)Bn II-393,5-Cl₂-phenyl

II-40 5-Br-phenyl CONH(3,4-F₂-phenyl) II-41 5-Cl-phenylCONH(2-OH-1-Ph-ethyl) II-42 4-OH,3-I,5-nitrophenyl CONH(2-OH-1-Ph-ethyl)II-43 5-Br-phenyl

II-44 3-NH₂,4-OH,5-I-phenyl CONH(2-OH-1-Ph-ethyl) II-45 5-Br-phenylCONH(2-OH-1-Ph-ethyl) II-46 5-Br-phenyl CONHCH₂(3-MeO-phenyl) II-475-Br-phenyl CONHCH₂(3-CF₃-phenyl) II-48 3,5-Cl₂-phenylCONHCH₂(pyrid-4-yl) II-49 5-CF₃-phenyl CONH(2-OH-1-Ph-ethyl) II-505-Cl-phenyl CONHCH₂Ph II-51 3,5-Cl₂-phenyl CONHOCH₂Ph II-524-OH,3-I,5-nitrophenyl CONHCH₂Ph II-53 5-Cl-phenyl CONHCH₂(pyrid-4-yl)II-54 4,5-Cl₂-phenyl CONHOCH₂Ph II-55 5-Br-phenylCONHCH₂(4-SO₂Me-phenyl) II-56 5-Br-phenyl CONHNH(3-CF₃-phenyl) II-575-Cl-phenyl CONHOCH₂Ph II-58 5-Br-phenyl

II-59 5-Br-phenyl

II-60 5-Br-phenyl CONHCH₂(2-Me-phenyl) II-61 4,5-Cl₂-phenylCONHCH₂(pyrid-4-yl) II-62 5-Br-phenyl CONH(1-Ph-propyl) II-63 5-F-phenylCONHCH₂Ph II-64 4,5-Cl₂-phenyl

II-65 5-Br-phenyl

II-66 3,5-Cl₂-phenyl CON(Me)(Et) II-67 5-Cl-phenyl CONHCH₂(pyrid-3-yl)II-68 5-Br-phenyl CONHCH₂(3,5-OMe₂-phenyl) II-69 5-Br-phenylCONHCH₂(2-OMe-phenyl) II-70 4-F-5-Cl-phenyl CONHCH₂(pyrid-4-yl) II-714-F-5-Cl-phenyl CON(Me)(Et) II-72 5-Br-phenyl CONH(2-OH-1-Ph-ethyl)II-73 5-NH₂-phenyl CONHCH₂Ph II-74 4,5-Cl₂-phenyl CONHCH₂(pyrid-3-yl)II-75 5-Me-phenyl CONH(2-OH-1-Ph-ethyl) II-76 3,5-Cl₂-phenylCONHCH₂(pyrid-3-yl) II-77 4-F-5-Cl-phenyl CONHOCH₂Ph II-783,5-Cl₂-phenyl CONHCH₂(tetrahydrofuran-2-yl) II-79 5-NO₂-phenylCONHCH₂Ph II-80 5-F-phenyl CONHCH₂(pyrid-4-yl) II-81 5-Cl-6-F-phenylCON(Me)(Et) II-82 2-F-3-Cl-phenyl CONHOCH₂Ph II-83 5-Br-phenyl

II-84 5-Cl-phenyl CONHCH₂(tetrahydrofuran-2-yl) II-85 4,5-F₂-phenylCONHOCH₂Ph II-86 5-Br-phenyl CONH(3-OH-1-Ph-propyl) II-87 5-Br-phenyl

II-88 4,5-F₂-phenyl CONHCH₂(pyrid-4-yl) II-89 5-F-phenyl CONHOCH₂PhII-90 5-Me-phenyl CONHCH₂Ph II-91 5-Br-phenyl

II-92 4-Cl-phenyl CONHCH₂Ph II-93 5-Cl-phenyl CON(Me)(Et) II-945-Br-phenyl CONHCH₂(4-SO₂NH₂-phenyl) II-95 5-OH-phenyl CONHCH₂Ph II-965-Me-phenyl CONHCH₂(pyrid-4-yl) II-97 Phenyl CONHCH₂Ph II-982,5-F₂-phenyl CONHCH₂(pyrid-4-yl) II-99 4-Cl-phenyl CONHOCH₂Ph II-1004-F-5-Cl-phenyl CONHCH₂(tetrahydrofuran-2-yl) II-101 4-F-5-Cl-phenylCONHCH₂(pyrid-3-yl) II-102 5-Br-phenyl

CO(4-OH-4-Ph-piperidin-1-yl) II-103 5,6-F₂-phenyl CONHOCH₂Ph II-1045-Cl-phenyl CO(morpholin-1-yl) II-105 5-Br-phenyl

II-106 2-F-3-Cl-phenyl CONHCH₂(tetrahydrofuran-2-yl) II-1074-F-5-Cl-phenyl CO(morpholin-1-yl) II-108 4-F-5-Cl-phenyl CON(Me)(Et)II-109 5-Br-phenyl CONHCH₂(4-NH₂-phenyl) II-110 5-Br-phenyl

II-111 4-F-phenyl CONHCH₂Ph II-112 3,5-Cl₂-phenyl CO(morpholin-1-yl)II-113 2,5-F₂-phenyl CONHOCH₂Ph II-114 2-F-3-Cl-phenylCONHCH₂(pyrid-3-yl) II-115 2-F-3-Cl-phenyl CONHCH₂(pyrid-4-yl) II-1164,5-F₂-phenyl CONHCH₂(pyrid-3-yl) II-117 4-OMe-phenyl CONHCH₂Ph II-1185-Br-phenyl CONHCH₂(2,4,6-OMe₃-phenyl) II-119 5-F-phenylCONHCH₂(pyrid-3-yl) II-120 4,5-F₂-phenyl CONHCH₂(tetrahydrofuran-2-yl)II-121 5-Cl-6-F-phenyl

II-122 5-Br-phenyl

II-123 5-Br-phenyl

II-124 5-Br-phenyl CONHCH₂(2,5-OMe₂-phenyl) II-125 3,5-Cl₂-phenyl

II-126 5-Br-phenyl

II-127 4,5-Cl₂-phenyl CO(morpholin-1-yl) II-128 5-Br-phenyl

II-129 2-F-3-Cl-phenyl CO(morpholin-1-yl) II-130 5-Br-phenylCONHCH₂CH₂OH II-131 5-NH₂-phenyl CONHCH₂Ph II-132 5-MeOC(O)-phenylCONHCH₂Ph II-133 4-MeO-phenyl CONHOCH₂Ph II-134 phenylCO(pyrrolidin-1-yl) II-135 5-MeO-phenyl CO(morpholin-1-yl) II-1365-Cl-phenyl CO(4-Me-piperidin-1-yl) II-137 5-NO₂-phenyl CONH₂NH₂ II-1385-Br-phenyl

II-139 5-Br-phenyl

II-140 5-Cl-phenyl CONHPh II-141 5,6-F₂-phenyl CONHCH₂(pyrid-4-yl)II-142 5-Cl-phenyl

II-143 phenyl CON(Me)₂ II-144 5-OMe-phenyl Co(pyrrolidin-1-yl) II-1455-OMe-phenyl CONHCH₂(pyrid-3-yl) II-146 4-F-phenyl CONHOCH₂Ph II-1475-OMe-phenyl CONHCH₂(furan-2-yl) II-148 5-NO₂-phenyl COOEt II-149 phenylCONHCH₂(furan-2-yl) II-150 phenyl CO(morpholin-1-yl) II-151 5-Cl-phenylCOOEt II-152 5-Br-phenyl CONHMe II-153 phenyl CONHCH₂(pyrid-3-yl) II-1545-OMe-phenyl CON(Me)₂ II-155 5-Cl-phenyl

II-156 5#Br-phenyl

II-157 5-Br-phenyl COOEt II-158 phenyl CONH(iPr) II-159 5-OMe-phenylCONH(iPr) II-160 5-COOH-phenyl CONH(iPr) II-161 5-Br-phenyl CONHO(iPr)II-162 5-F-phenyl COOEt II-163 5-OMe-phenyl CO(4-Me-piperidin-1-yl)II-164 4-NH₂-phenyl COOEt II-165 4-NO₂-phenyl COOEt II-166 phenyCO(4-Me-piperidin-1-yl) II-167 4-Cl-phenyl COOEt II-168 4-OMe-phenylCOOEt II-169 pheny COOEt II-170 5-OMe-phenyl COOEt II-171 4-F-phenylCOOEt II-172 5-NH₂-phenyl COOEt II-173 5-Cl-pheny1 COOH II-1745-Cl-phenyl

II-175 5-Cl-phenyl

II-176 5-OMe-phenyl CONHCH₂(pyrid-4-yl) II-177 3,5-(OMe)₂-phenylCONHCH₂(pyrid-4-yl) II-178 4-F-phenyl CONHCH₂(pyrid-3-yl) II-1794-OMe-phenyl CONHCH₂(pyrid-3-yl) II-180 2,5-(OM3)₂-phenylCONHCH₂(pyrid-3-yl) II-181 2,5-F₂-phenyl CONHCH₂(pyrid-3-yl) II-1824-F-phenyl CONHCH₂(tetrahydrofuran-2-yl) II-183 4-OMe-phenylCONHCH₂(tetrahydrofuran-2-yl) II-184 5-F-phenylCONHCH₂(tetrahydrofuran-2-yl) II-185 5-OMe-phenylCONHCH₂(tetrahydrofuran-2-yl) II-186 2,5-(OMe)₂-phenylCONHCH₂(tetrahydrofuran-2-yl) II-187 5,6-F₂-phenylCONHCH₂(tetrahydrofuran-2-yl) II-188 2,5-F₂-phenylCONHCH₂(tetrahydrofuran-2-yl) II-189 4-F-phenylCONHCH₂(1-Et-pyrrolidin-2-yl) II-190 4-OMe-phenylCONHCH₂(1-Et-pyrrolidin-2-yl) II-191 5-F-phenylCONHCH₂(1-Et-pyrrolidin-2-yl) II-192 5-OMe-phenylCONHCH₂(1-Et-pyrrolidin-2-yl) II-193 3,6-(OMe)₂-phenylCONHCH₂(1-Et-pyrrolidin-2-yl) II-194 4,5-F₂-phenylCONHCH₂(1-Et-pyrrolidin-2-yl) II-195 5,6-F₂-phenylCONHCH₂(1-Et-pyrrolidin-2-yl) II-196 3,6-F₂-phenylCONHCH₂(1-Et-pyrrolidin-2-yl) II-197 4-F-phenyl CO(morpholin-1-yl)II-198 4-OMe-phenyl CO(morpholin-1-yl) II-199 5-F-phenylCO(morpholin-1-yl) II-200 2,5-(OMe)₂-phenyl CO(morpholin-1-yl) II-2014,5-F₂-phenyl CO(morpholin-1-yl) II-202 5,6-F₂-phenyl CO(morpholin-1-yl)II-203 2,5-F₂-phenyl CO(morpholin-1-yl) II-204 4-F-phenylCO(4-Me-piperidin-1-yl) II-205 4-OMe-phenyl CO(4-Me-piperidin-1-yl)II-206 5-F-phenyl CO(4-Me-piperidin-1-yl) II-207 2,5-(OMe)₂-phenylCO(4-Me-piperidin-1-yl) II-208 4,5-F₂-phenyl CO(4-Me-piperidin-1-yl)II-209 5,6-F₂-phenyl CO(4-Me-piperidin-1-yl) II-210 3,6-F₂-phenylCO(4-Me-piperidin-1-yl) II-211 4-Cl-phenyl CONHCH₂(pyrid-4-yl) II-2124,5-(OMe)₂-phenyl CONHCH₂(pyrid-4-yl) II-213 4-benzo[1,3]dioxo-5-ylCONHCH₂(pyrid-4-yl) II-214 4-Cl-phenyl CONHCH₂(pyrid-3-yl) II-2154,5-(OMe)₂-phenyl CONHCH₂(pyrid-3-yl) II-216 4-benzo[1,3]dioxo-5-ylCONHCH₂(pyrid-3-yl) II-217 4-Cl-phenyl CONHCH₂(tetrahydrofuran-2-yl)II-218 4,5-(OMe)₂-phenyl CONHCH₂(tetrahydrofuran-2-yl) II-2194-benzo[1,3]dioxo-5-yl CONHCH₂(tetrahydrofuran-2-yl) II-220 4-Cl-phenylCONHCH₂(1-Et-pyrrolidin-2-yl) II-221 4,5-Cl₂-phenylCONHCH₂(1-Et-pyrrolidin-2-yl) II-222 5-Cl-6-F-phenylCONHCH₂(1-Et-pyrrolidin-2-yl) II-223 4-F-5-Cl-phenylCONHCH₂(1-Et-pyrrolidin-2-yl) II-224 4,5-(OMe)₂-phenylCONHCH₂(1-Et-pyrrolidin-2-yl) II-225 4-benzo[1,3]dioxo-5-ylCONHCH₂(1-Et-pyrrolidin-2-yl) II-226 3,5-Cl₂-phenylCONHCH₂(1-Et-pyrrolidin-2-yl) II-227 4-Cl-phenyl CO(morpholin-1-yl)II-228 4,5-(OMe)₂-phenyl CO(morpholin-1-yl) II-2294-benzo[1,3]dioxo-5-yl CO(morpholin-1-yl) II-230 4-Cl-phenylCO(4-Me-piperidin-1-yl) II-231 4,5-Cl₂-phenyl CO(4-Me-piperidin-1-yl)II-232 5-Cl-6-F-phenyl CO(4-Me-piperidin-1-yl) II-233 4-F-5-Cl-phenylCO(4-Me-piperidin-1-yl) II-234 4,5-(OMe)₂-phenyl CO(4-Me-piperidin-1-yl)II-235 4-benzo[1,3]dioxo-5-yl CO(4-Me-piperidin-1-yl) II-2363,5-Cl₂-phenyl CO(4-Me-piperidin-1-yl) II-237 5,6-F₂-phenyl CON(Me)(Et)II-238 4-F-phenyl

II-239 5-OMe-phenyl

II-240 2,5-(OMe)₂-phenyl

II-241 4,5-F₂-phenyl

II-242 5,6-F₂-phenyl

II-243 3,6-F₂-phenyl

II-244 5-MeO-phenyl CONHOCH₂Ph II-245 2,5-(OMe)₂-phenyl CONHOCH₂PhII-246 5-F-phenyl

II-247 5-MeO-phenyl

II-248 4,5-F₂-phenyl

II-249 5,6-F₂-phenyl

II-250 5-Cl-phenyl

II-251 4-C]-phenyl

II-252 4-Cl-phenyl

II-253 4,5-Cl₂-phenyl

II-254 4,5-Cl₂-pheny]

II-255 2-F-3-Cl-phenyl

II-256 4-F-5-Cl-phenyl

II-257 4-F-5-Cl-phenyl

II-258 4,5-(OMe)₂-phenyl CON(Me)(Et) II-259 4,5-(OMe)₂-phenyl

II-260 4,5-(OMe)₂-phenyl CONHOCH₂Ph II-261 4,5-(OMe)₂-phenyl

II-262 4-benzo[1,3]dioxo-5-yl CON(Me)(Et) II-263 4-benzo[1,3]dioxo-5-yl

II-264 4-benzo[1,3]dioxo-5-yl CONHOCH₂Ph II-265 4-benzo[1,3]dioxo-5-yl

II-266 3,5-Cl₂-phenyl

II-267 5-Br-phenyl

II-268 5-Br-phenyl

II-269 5-Br-phenyl

II-270 5-Br-phenyl

II-271 5-Br-phenyl

II-272 5-Br-phenyl

II-273 5-Br-phenyl

II-274 5-Br-phenyl

II-275 5-Br-phenyl

II-276 5-Br-phenyl

II-277 5-Br-phenyl

II-278 5-Br-phenyl

II-279 5-Br-phenyl

II-280 5-Br-phenyl CONH(CH₂)₂COOH II-281 5-Br-phenyl

II-282 5-Br-phenyl CONHCH₂(4-COOH-phenyl) II-283 5-Br-phenyl

II-284 5-Br-phenyl

II-285 3-NO₂-phenyl CONHCH₂phenyl II-286 5-Cl-phenylCONHCH₂(1-Et-pyrrolidin-2-yl) II-287 5-(N—Et—NHCO)-phenyl CONHCH₂phenylII-288 5-Br-phenyl

II-289 5-NO₂-phenyl CONHCH₂(pyrid-4-yl) II-290 5-Br-phenyl

II-291 5-F-phenyl CON(Me)(Et) II-292 5-MeO-phenyl CON(Me)(Et) II-2935-Br-phenyl

II-294 5-Br-phenyl

II-295 5-Br-phenyl

II-296 5-Br-phenyl

II-297 phenyl CONH(CH₂)₂NMe₂ II-298 5-MeO-phenyl CONH(CH₂)₂NMe₂ II-2995-Br-phenyl CONHCH₂phenyl II-300 3-Cl-phenyl

II-301 3#Cl-phenyl

II-302 3-Cl-phenyl

II-303 3-Cl-phenyl

II-304 3-Cl-phenyl

II-305 3-Cl-phenyl

II-306 3-Cl-phenyl

II-307 3-Cl-phenyl

II-308 3-Cl-phenyl

II-309 3-Cl-phenyl

II-310 3,5-Cl₂-phenyl

II-311 3-Br-5-CF₃-phenyl

II-312 3-Cl-phenyl

II-313 3,5-Cl₂-phenyl

II-314 3-Cl-4-CN-phenyl

II-315 3-Cl-4-CH₂OH-phenyl

II-316 3-Cl-4-CH₂NH₂-phenyl

II-317

II-318

II-319

II-320

II-321

II-322

II-323 CH₂Ph CON(Me)₂ II-324 cyclopentylmethyl CO₂NHCH₂Ph II-325isopropyl CN II-326 3-Cl-phenyl NHCOCH₂Ph II-327 3-Cl-phenylNHSO₂-morpholin-1-yl II-328 3-Cl-phenyl NHCONHCH₂Ph II-329 3-Cl-phenylNHCO₂-tetrahydrofuran-2-yl II-330 CH₂Ph CONHCH₂Ph II-331 Me CONHCH₂PhII-332 isopropyl CONHCH₂Ph II-333 H CON(Me)₂

Another preferred embodiment of this invention relates to compounds offormula II-B:

wherein T, R, R², and R⁴ are as described above.

Preferred II-B compounds include those having one or more, and mostpreferably all, of the following features: (a) T is a valence bond; (b)R³ is hydrogen; and/or (c) R₂ is an optionally substituted aryl ring,more preferably an optionally substituted phenyl ring.

Exemplary structures of formula II-B, wherein R³ is H, are set out inTable 2 below.

TABLE 2 Compounds II-B No. R T-R² Q-R⁴ II-B-1  H phenyl CON(Me)₂ II-B-2 H phenyl CO₂Et II-B-3  H 3-NO₂-phenyl CONHNH₂ II-B-4  H phenylCO(pyrrolidin-1-yl) II-B-5  Me phenyl CONHCH₂(Ph) II-B-6  H 3-NO₂-phenylCO₂Et II-B-7  H 4-Cl-phenyl CO₂Et II-B-8  Me 4-OMe-phenyl CO₂Et II-B-9 H 3-NH₂-phenyl CO₂Et II-B-10 H 3-OMe-phenyl CO₂Et II-B-11 H 4-F-phenylCO₂Et II-B-12 H 4-NO₂-phenyl CO₂Et II-B-13 Et 3-Cl-phenyl CO₂Et II-B-14H 3-F-phenyl CO₂Et II-B-15 H phenyl CO₂H II-B-16 Me 3-Cl-phenylCONHCH₂(pyridin-4-yl) II-B-17 H 5-Cl-phenyl

II-B-18 H 5-F-phenyl CONHCH₂(tetrahydrofuran-2-yl) II-B-19 Me5,6-F₂-phenyl CO(4-Me-piperidin-1-yl) II-B-20 H 4-Cl-phenylCONHCH₂(pyrid-4-yl) II-B-21 H 4,5-(OMe)₂-phenyl

II-B-22 Me 4,5-Cl₂-phenyl

II-B-23 H 3-Cl-phenyl

II-B-24 H 3-Cl-phenyl

II-B-25 Me 3,5-Cl₂-phenyl

II-B-26 H

II-B-27 H H CON(Me)₂

The present compounds may be prepared in general by methods known tothose skilled in the art for analogous compounds, as illustrated by thegeneral Schemes I and II and the synthetic examples shown below.

Reagents and conditions: (a) PhCH₂COCl, AlCl₃, CH₂Cl₂, 2 hours, RT (b)DMF, 24 hrs, room temperature (c) (Me₂N)₂-To-Bu, THF, 24 hrs, roomtemperature (d) H₂NNH₂, EtOH, 12 hours, reflux.

Scheme I above shows a general synthetic route that was used forpreparing the compounds of this invention when R² is an optionallysubstituted phenyl group. In step (a), an optionally substituted benzoylchloride was combined with compound 1 in dichloromethane and aluminumtrichloride to form compound 2. A wide variety of substitutions on thephenyl ring are amenable to this reaction. Examples of suitable R²groups include, but are not limited to, those set forth in Table 1above.

The formation of amide 4 was achieved by treating compound 2 with anamine 3 in DMF. When amine 3 was a primary amine, the reaction proceededat ambient temperature. When amine 3 was a secondary amine, the reactionwas heated at 50° C. to achieve complete reaction and afford amide 4.

The formation of enamine 5 at step (c) was achieved by treating amide 4with (Me₂N)₂-To-Bu at ambient temperature. Alternatively, the reactionto form enamine 5 at step (c) was also achieved by usingdimethylformamide-dimethylacetal (DMF-DMA). The reaction using DMF-DMArequires elevated temperature to afford enamine 5 whereas using(Me₂N)₂-OtBu has the advantage of proceeding at ambient temperature toafford the enamine 5 in higher purity.

The formation of the pyrazole compound 6 at step (d) was achieved by thetreatment of enamine 5 with hydrazine hydrate at elevated temperature.The compounds of formula II synthesized by this method, as exemplifiedin Table 1, were isolated by preparatory HPLC (reverse phase, 10→90%MeCN in water over 15 minutes). The details of the conditions used forproducing these compounds are set forth in the Examples.

Reagents and conditions: (a) 3-Cl—PhCH₂COCl, AlCl₃, CH₂Cl₂, 2 hours, RT(b) DMF, 24 hrs, room temperature (c) NBS, CCl₄, reflux (d) iPrOH,reflux (e) formic acid, reflux, 2 hours.

Scheme II above shows a general synthetic method that may be used forpreparing compounds of formula II-B, using compound II-B-16 as anexample. This method is modified from that of Jira, T., et al,Pharmazie, pp. 401-406 (1994). Compounds of formula II-B may also beprepared by methods similar to those of Woller, J., et al, Pharmazie,pp. 937-940 (1996), Rychmans, T., et al, Tetrahedron, pp. 1729-1734(1997), and Tupper, D. E., et al, Synthesis, pp. 337-341 (1997).

According to another embodiment, the invention provides a method ofinhibiting kinase activity in a biological sample. This method comprisesthe step of contacting said biological sample with a compound of thisinvention.

The term “biological sample”, as used herein includes cell cultures orextracts thereof; biopsied material obtained from a mammal or extractsthereof; and blood, saliva, urine, feces, semen, tears, or other bodyfluids or extracts thereof. The term “biological sample” also includesliving organisms, in which case “contacting a compound of this inventionwith a biological sample” is synonymous with the term “administratingsaid compound (or composition comprising said compound) to a mammal.”

Another aspect of this invention relates to a method for treating adisease state in mammals that is alleviated by treatment with a proteinkinase inhibitor, which method comprises administering to a mammal inneed of such a treatment a therapeutically effective amount of acompound having the formula

or a pharmaceutically acceptable derivative thereof, wherein:

R¹ is selected from R, halogen, N(R⁸)₂, OR, NRCOR, NRCON(R⁸)₂, CON(R⁸)₂,SO₂R, NRSO₂R, or SO₂N(R⁸)₂;

T is selected from a valence bond or a linker group;

each R is independently selected from hydrogen or an optionallysubstituted aliphatic group having one to six carbons;

R² is selected from hydrogen, CN, halogen, aryl, aralkyl, heteroaryl,heterocyclyl, an optionally substituted acyclic aliphatic chain grouphaving one to six carbons, or an optionally substituted cyclic aliphaticgroup having four to ten carbons;

R³ is selected from R, OH, OR, N(R⁸)₂, halogen, or CN;

Q is a valence bond, J, or an optionally substituted C₁₋₆ alkylidenechain wherein up to two nonadjacent carbons of the alkylidene chain areeach optionally and independently replaced by J;

J is selected from —C(═O)—, —CO₂—, —C(O)C(O)—, —NRCONR⁸—, —N(R)N(R⁸)—,—C(═O)NR⁸—, —NRC(═O)—, —O—, —S—, —SO—, —SO₂—, —N(R)O—, —ON(R⁸)—,—OC(═O)N(R⁸)—, —N(R)COO—, —SO₂N(R⁸)—, —N(R)SO₂—, or —N(R⁸)—;

R⁴ is selected from —R⁸, —R⁵, —NH₂, —NHR⁵, —N(R⁵)₂, or —NR⁵(CH₂)_(y)N(R⁵)₂;

each R⁵ is independently selected from R⁶, R⁷, —(CH₂)_(y)CH(R⁶)(R⁷),—(CH₂)_(y)R⁶, —(CH₂)_(y)CH(R⁶)₂, —(CH₂)_(y)CH(R⁷)₂, or —(CH₂)_(y)R⁷;

y is 0-6;

each R⁶ is an optionally substituted group independently selected froman aliphatic, aryl, aralkyl, aralkoxy, heteroaryl, heteroarylalkyl,heteroarylalkoxy, heterocyclyl, heterocyclylalkyl, orheterocyclylalkoxy, group;

each R⁷ is independently selected from an optionally substitutedaliphatic, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, or alkoxycarbonyl;

and each R⁸ is independently selected from R, or two R⁸ on the samenitrogen taken together with the nitrogen optionally form a four toeight membered, saturated or unsaturated heterocyclic ring having one tothree heteroatoms.

One embodiment comprises administering a compound of formula II. Apreferred embodiment comprises administering a compound of formula II-A,and most preferably a compound listed in Table 1. Another preferredembodiment comprises administering a compound of formula II-B, and morepreferably a compound listed in Table 2. Pharmaceutical compositionsuseful for such methods are described below.

The present method is especially useful for treating a disease statethat is alleviated by the use of an inhibitor of ERK, JAK, JNK, Aurora,GSK, KDR, or AKT. As used herein, unless otherwise indicated, the terms“ERK”, “JAK”, “JNK”, “Aurora”, “GSK”, “KDR”, and “AKT” refer to allisoforms of the respective enzymes including, but not limited to, ERK1,ERK2, ERK3, ERK4, ERK5, ERK6, ERK7, JAK1, JAK2, JAK3, JAK4, JNK1, JNK2,JNK3, Auroral, Aurora2, GSK3-alpha, GSK3-beta, KDR, AKT-1, AKT-2, andAKT-3.

The activity of the compounds as protein kinase inhibitors, for exampleas ERK inhibitors, may be assayed in vitro, in vivo or in a cell line.Using ERK as an example, in vitro assays include assays that determineinhibition of either the kinase activity or ATPase activity of activatedERK. Alternate in vitro assays quantitate the ability of the inhibitorto bind to ERK and may be measured either by radiolabelling theinhibitor prior to binding, isolating the inhibitor/ERK complex anddetermining the amount of radiolabel bound, or by running a competitionexperiment where new inhibitors are incubated with ERK bound to knownradioligands. one may use any type or isoform of ERK, depending uponwhich ERK type or isoform is to be inhibited.

The compounds of this invention are potent inhibitors of ERK asdetermined by enzymatic assay. These compounds have also been shown toinhibit ERK in a cell proliferation assay. The details of the conditionsused for both the enzymatic and the cell proliferation assays are setforth in the Examples hereinbelow.

The compounds of this invention are also inhibitors of JNK, Aurora, GSK,KDR, and AKT as determined by enzymatic assay. The details of theconditions used for this assay are set forth in the Exampleshereinbelow. Without being bound by theory, the compounds of thisinvention are also expected to inhibit other protein kinases.

The protein kinase inhibitors of this invention, or pharmaceutical saltsthereof, may be formulated into pharmaceutical compositions foradministration to animals or humans. These pharmaceutical compositionseffective to treat or prevent a protein kinase-mediated condition whichcomprise the protein kinase inhibitor in an amount sufficient todetectably inhibit protein kinase activity and a pharmaceuticallyacceptable carrier, are another embodiment of the present invention. Theterm “detectably inhibit”, as used herein means a measurable change inactivity between a sample containing said inhibitor and a samplecontaining only a protein kinase.

The term “ERK-mediated condition”, as used herein means any diseasestate or other deleterious condition in which ERK is known to play arole. Such conditions include, without limitation, cancer, stroke,diabetes, hepatomegaly, cardiovascular disease including cardiomegaly,Alzheimer's disease, cystic fibrosis, viral disease, autoimmunediseases, atherosclerosis, restenosis, psoriasis, allergic disordersincluding asthma, inflammation, neurological disorders andhormone-related diseases. The term “cancer” includes, but is not limitedto the following cancers: breast, ovary, cervix, prostate, testis,genitourinary tract, esophagus, larynx, glioblastoma, neuroblastoma,stomach, skin, keratoacanthoma, lung, epidermoid carcinoma, large cellcarcinoma, small cell carcinoma, lung adenocarcinoma, bone, colon,adenoma, pancreas, adenocarcinoma, thyroid, follicular carcinoma,undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma,sarcoma, bladder carcinoma, liver carcinoma and biliary passages, kidneycarcinoma, myeloid disorders, lymphoid disorders, Hodgkin's, hairycells, buccal cavity and pharynx (oral), lip, tongue, mouth, pharynx,small intestine, colon-rectum, large intestine, rectum, brain andcentral nervous system, and leukemia.

Compounds of the present invention are also useful as inhibitors ofrelated kinases. The term “related kinases” refer to protein kinaseshaving residues which are similar to those residues which line the ERKbinding site. Without wishing to be bound by theory, applicantsspeculate that this inhibitory activity is due to the close structuralsimilarity between the active sites of ERK and related kinases. Thealignment of the ERK sequence with other kinases can be derived fromcommon software programs such as the “bestfit” program available fromGenetics Computer Group. This program uses the local homology algorithmdescribed by Smith and Waterman in Advances in Applied Mathematics 2;482 (1981).

Related kinases inhibited by the compounds of this invention wouldcontain residues, identified by the above standard protein sequencealignment software, corresponding to the ERK residues: I31, E33, G34,A35, Y36, G37, M38, V39, A52, K54, R67, T68, E71, L75, I84, I86, I103,Q105, D106, L107, M108, E109, D111, K114, D149, K151, S153, N154, L156,C166, and D167, with a similarity score of 80% or greater. Thesimilarity score may be determined using standard amino acidsubstitution tables such as those described by Dayhoff (Dayhoff, M. O.,et al, Atlas of Protein Sequence and Structure, 1979) andBlosom-Henikoff (Blosum-Henikoff, S and Henikoff, J. G., PNAS,1992,89:10915-10919). The term “related kinases” also includes thosecontaining residues with a similarity score of 80% or greater to thefollowing ERK residues: I31, G37, A52, I103, E109, and N154.

Compounds of the present invention are also useful as inhibitors ofJAK-family kinases. Without wishing to be bound by theory, applicantsspeculate that this inhibitory activity is due to the close structuralsimilarity between the active sites of ERK and JAK as determined by thestandard methods described above.

It has been found, from in-house x-ray crystal structure experimentswith ERK-bound inhibitors, that three amino-acid residues in the ERKactive site form key hydrogen bonding interactions with these types ofinhibitors. These three amino-acid residues are M108, D106, and Q105.This amino acid numbering corresponds to the Swiss-Prot database entryfor accession #P28482. The Swiss-Prot database is an internationalprotein sequence database distributed by the European BioinformaticsInstitute (EBI) in Geneva, Switzerland. The database can be found atwww.ebi.ac.uk/swissprot.

The backbone atoms of M108 and D106, and the associated interactions,are common to all kinases. M108 provides both a hydrogen bond donor andacceptor and D106 provides a hydrogen bond acceptor through its backboneCO. An inhibitor that could form a hydrogen-bond to one or more of thesehydrogen-bonding groups within the active site would be expected to bindto the enzyme and, therefore, show inhibition.

The Q105 glutamine residue is implicated in a subset of kinases thatincludes ERK and JAK as determined by examination of the alignment dataobtained from the above mentioned software programs. Q105 provides a keyhydrogen-bond accepting side-chain Co. Modeling experiments reveal thatfor both ERK and JAK, the hydrogen bond donor of the Ht-ring is withinhydrogen-bonding distance to the Q105 residue. Because of these similaractive-site interactions, the ERK inhibitors of the present inventioninhibit JAK as well. Accordingly, these compounds are useful fortreating JAK-mediated conditions.

The term “JAK-mediated condition”, as used herein, means any diseasestate or other deleterious 15 condition in which JAK is known to play arole. Such conditions include, without limitation, allergic disorderssuch as asthma and atopic dermatitis, autoimmune diseases such as SLElupus and psoriasis, and conditions associated with organtransplantations.

The compounds of this invention are also useful as inhibitors ofJNK-family kinases. Accordingly, these compounds are useful for treatingJNK-mediated conditions. The term “JNK-mediated condition”, as usedherein, means any disease state or other deleterious condition in whichJNK is known to play a role. Such conditions include, withoutlimitation, apoptosis-driven neurodegenerative diseases such asAlzheimer's Disease, Parkinson's Disease, ALS (Amyotrophic LateralSclerosis), epilepsy and seizures, Huntington's Disease, traumatic braininjuries, as well as ischemic and hemorrhaging stroke, heart disease,immunodeficiency disorders, inflammatory diseases, allergic disorders,autoimmune diseases, destructive bone disorders such as osteoporosis,proliferative disorders, infectious diseases, viral diseases, disordersrelating to cell death and hyperplasia including reperfusion/ischemia instroke, heart attacks, and organ hypoxia, thrombin-induced plateletaggregation, chronic myelogenous leukemia (CML), rheumatoid arthritis,asthma, osteoarthritis, ischemia, cancer, liver disease includinghepatic ischemia, heart disease such as myocardial infarction andcongestive heart failure, pathologic immune conditions involving T cellactivation and neurodegenerative disorders.

The compounds of this invention are also useful as inhibitors of Aurora.Accordingly, these compounds are useful for treating Aurora-mediatedconditions. The term “Aurora-mediated condition”, as used herein, meansany disease or other deleterious condition in which Aurora is known toplay a role. Such conditions include, without limitation, cancer. Theterm “cancer” includes, but is not limited to the following cancers:colon and ovarian.

The compounds of this invention are also useful as inhibitors of GSKfamily kinases. Accordingly, these compounds are useful for treatingGSK-mediated conditions. The term “GSK-mediated condition”, as usedherein, means any disease state or other deleterious condition in whichGSK is known to play a role. Such conditions include, withoutlimitation, diabetes, Alzheimers disease, neurodegenerative diseases,and CNS disorders such as manic depressive disorder and schizophrenia.

The compounds of this invention are also useful as inhibitors of KDRfamily kinases. Accordingly, these compounds are useful for treatingKDR-mediated conditions. The term “KDR-mediated condition”, as usedherein, means any disease state or other deleterious condition in whichKDR is known to play a role. KDR-mediated diseases or conditionsinclude, but are not limited to, cancer such as brain cancer,genitourinary tract cancer, lymphatic system cancer, stomach cancer,cancer of the larynx, lung cancer, pancreatic cancer, breast cancer,Kaposils sarcoma, and leukemia; endometriosis, benign prostatichyperplasia; vascular diseases such as restenosis and atherosclerosis;autoimmune diseases such as rheumatoid arthritis and psoriasis; ocularconditions such as proliferative or angiogenic retinopathy and maculardegeneration; and inflammatory diseases such as contact dermatitis,asthma and delayed hypersensitivity reactions.

The compounds of this invention are also useful as inhibitors of AKTfamily kinases. Accordingly, these compounds are useful for treatingAKT-mediated conditions. The term “AKT-mediated condition”, as usedherein, means any disease state or other deleterious condition in whichAKT is known to play a role. AKT-mediated diseases or conditionsinclude, but are not limited to, proliferative disorders, cancer, andneurodegenerative disorders.

In addition to the compounds of this invention, pharmaceuticallyacceptable derivatives or prodrugs of the compounds of this inventionmay also be employed in compositions to treat or prevent theabove-identified disorders.

A “pharmaceutically acceptable derivative or prodrug” means anypharmaceutically acceptable salt, ester, salt of an ester or otherderivative of a compound of this invention which, upon administration toa recipient, is capable of providing, either directly or indirectly, acompound of this invention or an inhibitorily active metabolite orresidue thereof. Particularly favored derivatives or prodrugs are thosethat increase the bioavailability of the compounds of this inventionwhen such compounds are administered to a mammal (e.g., by allowing anorally administered compound to be more readily absorbed into the blood)or which enhance delivery of the parent compound to a biologicalcompartment (e.g., the brain or lymphatic system) relative to the parentspecies.

Pharmaceutically acceptable prodrugs of the compounds of this inventioninclude, without limitation, esters, amino acid esters, phosphateesters, metal salts and sulfonate esters.

Pharmaceutically acceptable salts of the compounds of this inventioninclude those derived from pharmaceutically acceptable inorganic andorganic acids and bases. Examples of suitable acid salts includeacetate, adipate, alginate, aspartate, benzoate, benzenesulfonate,bisulfate, butyrate, citrate, camphorate, camphorsulfonate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptanoate, glycerophosphate, glycolate,hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmoate,pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate,propionate, salicylate, succinate, sulfate, tartrate, thiocyanate,tosylate and undecanoate. Other acids, such as oxalic, while not inthemselves pharmaceutically acceptable, may be employed in thepreparation of salts useful as intermediates in obtaining the compoundsof the invention and their pharmaceutically acceptable acid additionsalts.

Salts derived from appropriate bases include alkali metal (e.g., sodiumand potassium), alkaline earth metal (e.g., magnesium), ammonium and N⁺(C₁₋₄ alkyl)₄ salts. This invention also envisions the quaternization ofany basic nitrogen-containing groups of the compounds disclosed herein.Water or oil-soluble or dispersible products may be obtained by suchquaternization.

Pharmaceutically acceptable carriers that may be used in thesepharmaceutical compositions include, but are not limited to, ionexchangers, alumina, aluminum stearate, lecithin, serum proteins, suchas human serum albumin, buffer substances such as phosphates, glycine,sorbic acid, potassium sorbate, partial glyceride mixtures of saturatedvegetable fatty acids, water, salts or electrolytes, such as protaminesulfate, disodium hydrogen phosphate, potassium hydrogen phosphate,sodium chloride, zinc salts, colloidal silica, magnesium trisilicate,polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol,sodium carboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat.

The compositions of the present invention may be administered orally,parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. The term “parenteral”as used herein includes subcutaneous, intravenous, intramuscular,intra-articular, intra-synovial, intrasternal, intrathecal,intrahepatic, intralesional and intracranial injection or infusiontechniques. Preferably, the compositions are administered orally,intraperitoneally or intravenously.

Sterile injectable forms of the compositions of this invention may beaqueous or an oleaginous suspension. These suspensions may be formulatedaccording to techniques known in the art using suitable dispersing orwetting agents and suspending agents. The sterile injectable preparationmay also be a sterile injectable solution or suspension in a non-toxicparenterally-acceptable diluent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose, any bland fixed oilmay be employed including synthetic mono- or di-glycerides. Fatty acids,such as oleic acid and its glyceride derivatives are useful in thepreparation of injectables, as are natural pharmaceutically-acceptableoils, such as olive oil or castor oil, especially in theirpolyoxyethylated versions. These oil solutions or suspensions may alsocontain a long-chain alcohol diluent or dispersant, such ascarboxymethyl cellulose or similar dispersing agents which are commonlyused in the formulation of pharmaceutically acceptable dosage formsincluding emulsions and suspensions. Other commonly used surfactants,such as Tweens, Spans and other emulsifying agents or bioavailabilityenhancers which are commonly used in the manufacture of pharmaceuticallyacceptable solid, liquid, or other dosage forms may also be used for thepurposes of formulation.

The pharmaceutical compositions of this invention may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, aqueous suspensions or solutions. In thecase of tablets for oral use, carriers commonly used include lactose andcorn starch. Lubricating agents, such as magnesium stearate, are alsotypically added. For oral administration in a capsule form, usefuldiluents include lactose and dried cornstarch. When aqueous suspensionsare required for oral use, the active ingredient is combined withemulsifying and suspending agents. If desired certain sweetening,flavoring or coloring agents may also be added.

Alternatively, the pharmaceutical compositions of this invention may beadministered in the form of suppositories for rectal administration.These can be prepared by mixing the agent with a suitable non-irritatingexcipient which is solid at room temperature but liquid at rectaltemperature and therefore will melt in the rectum to release the drug.Such materials include cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions of this invention may also beadministered topically, especially when the target of treatment includesareas or organs readily accessible by topical application, includingdiseases of the eye, the skin, or the lower intestinal tract. Suitabletopical formulations are readily prepared for each of these areas ororgans.

Topical application for the lower intestinal tract can be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches may also be used.

For topical applications, the pharmaceutical compositions may beformulated in a suitable ointment containing the active componentsuspended or dissolved in one or more carriers. Carriers for topicaladministration of the compounds of this invention include, but are notlimited to, mineral oil, liquid petrolatum, white petrolatum, propyleneglycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax andwater. Alternatively, the pharmaceutical compositions can be formulatedin a suitable lotion or cream containing the active components suspendedor dissolved in one or more pharmaceutically acceptable carriers.Suitable carriers include, but are not limited to, mineral oil, sorbitanmonostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol,2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutical compositions may be formulated asmicronized suspensions in isotonic, pH adjusted sterile saline, or,preferably, as solutions in isotonic, pH adjusted sterile saline, eitherwith or without a preservative such as benzylalkonium chloride.Alternatively, for ophthalmic uses, the pharmaceutical compositions maybe formulated in an ointment such as petrolatum.

The pharmaceutical compositions of this invention may also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

The amount of protein kinase inhibitor of this invention that may becombined with the carrier materials to produce a single dosage form willvary depending upon the host treated, the particular mode ofadministration. Preferably, the compositions should be formulated sothat a dosage of between about 0.01-100 mg/kg body weight/day of theinhibitor can be administered to a patient receiving these compositions.

It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health, sex, diet, time of administration,rate of excretion, drug combination, and the judgment of the treatingphysician and the severity of the particular disease being treated. Theamount of inhibitor will also depend upon the particular compound in thecomposition.

The kinase inhibitors of this invention or pharmaceutical compositionsthereof may also be incorporated into compositions for coating animplantable medical device, such as prostheses, artificial valves,vascular grafts, stents and catheters. Vascular stents, for example,have been used to overcome restenosis (re-narrowing of the vessel wallafter injury). However, patients using stents or other implantabledevices risk clot formation or platelet activation. These unwantedeffects may be prevented or mitigated by pre-coating the device with acomposition comprising a kinase inhibitor. Suitable coatings and thegeneral preparation of coated implantable devices are described in U.S.Pat. Nos. 6,099,562; 5,886,026; and 5,304,121. The coatings aretypically biocompatible polymeric materials such as a hydrogel polymer,polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylacticacid, ethylene vinyl acetate, and mixtures thereof. The coatings mayoptionally be further covered by a suitable topcoat of fluorosilicone,polysaccarides, polyethylene glycol, phospholipids or combinationsthereof to impart controlled release characteristics in the composition.Implantable devices coated with a kinase inhibitor of this invention areanother embodiment of the present invention.

According to another embodiment, the invention provides methods fortreating or preventing an ERK-, JAK-, JNK-, Aurora-, GSK-, KDR-, orAKT-mediated condition, or disease state, comprising the step ofadministering to a patient one of the above-described pharmaceuticalcompositions. The term “patient”, as used herein, means a mammal,preferably a human.

Preferably, that method is used to treat or prevent a condition, ordisease state, selected from cancers such as cancers of the breast,colon, prostate, skin, pancreas, brain, genitourinary tract, lymphaticsystem, stomach, larynx and lung, including lung adenocarcinoma andsmall cell lung cancer, stroke, diabetes, hepatomegaly,cardiomegaly,cardiovascular disease, Alzheimer's disease, cysticfibrosis, and viral disease, or any specific disease or disorderdescribed above.

Depending upon the particular condition, or disease state, to be treatedor prevented, additional therapeutic agents, which are normallyadministered to treat or prevent that condition, may be administeredtogether with the inhibitors of this invention. For example,chemotherapeutic agents or other anti-proliferative agents may becombined with the inhibitors of this invention to treat proliferativediseases and cancer. Examples of known chemotherapeutic agents include,but are not limited to, adriamycin, dexamethasone, vincristine,cyclophosphamide, fluorouracil, topotecan, taxol, interferons, andplatinum derivatives.

Other examples of agents the inhibitors of this invention may also becombined with include, without limitation, anti-inflammatory agents suchas corticosteroids, TNF blockers, IL-1 RA, azathioprine,cyclophosphamide, and sulfasalazine; immunomodulatory andimmunosuppressive agents such as cyclosporin, tacrolimus, rapamycin,mycophenolate mofetil, interferons, corticosteroids, cyclophophamide,azathioprine, and sulfasalazine; neurotrophic factors such asacetylcholinesterase inhibitors, MAO inhibitors, interferons,anti-convulsants, ion channel blockers, riluzole, and anti-Parkinsonianagents; agents for treating cardiovascular disease such asbeta-blockers, ACE inhibitors, diuretics, nitrates, calcium channelblockers, and statins; agents for treating liver disease such ascorticosteroids, cholestyramine, interferons, and anti-viral agents;agents for treating blood disorders such as corticosteroids,anti-leukemic agents, and growth factors; agents for treating diabetessuch as insulin, insulin analogues, alpha glucosidase inhibitors,biguanides, and insulin sensitizers; and agents for treatingimmunodeficiency disorders such as gamma globulin.

These additional agents may be administered separately, as part of amultiple dosage regimen, from the inhibitor-containing composition.Alternatively, these agents may be part of a single dosage form, mixedtogether with the inhibitor in a single composition.

In order that the invention described herein may be more fullyunderstood, the following examples are set forth. It should beunderstood that these examples are for illustrative purposes only andare not to be construed as limiting this invention in any manner.

EXAMPLES Example 1

2,2,2-Trichloro-1-(4-phenylacetyl-1H-pyrrol-2-yl)-ethanone (1): In a dryflask, phenylacetyl chloride (1 equivalent) was combined with2-trichloroacetyl pyrrole (1 equivalent) in a minimum amount ofdichloromethane (DCM). To the resulting solution, at ambienttemperature, was added aluminum trichloride (1 equivalent). After 2hours, the reaction mixture was applied directly onto a silica gelcolumn. Gradient elution with 10% ethyl acetate to 50% ethyl acetate inhexanes provided compound 1 in 60% yield. ¹H NMR (CDCl₃) δ 4.0 (s, 2H),7.1-7.35 (m, 7H), 9.7 (br s, NH). HPLC using method B (as describedbelow for Example 5) provided retention time of 4.9 minutes. LC/MS (M+1)330.2, (M−1) 328.1.

Example 2

4-Phenylacetyl-1H-pyrrole-2-carboxylic acid benzylamide (2): To asolution of compound 1 (1 equivalent) in DMF, at ambient temperature,was added benzylamine (1.2 equivalents). After 24 hours, the solvent wasevaporated and the crude product 2 was utilized without purification.HPLC using method B (as described below for Example 5) providedretention time of 3.8 minutes. FIA/MS (M+1) 319.3, (M−1) 317.2.

Example 3

4-(3-Dimethylamino-2-phenyl-acryloyl)-1H-pyrrole-2-carboxylic acidbenzylamide (3): To a solution of compound 2 (1 equivalent) in THF, atambient temperature, was added (Me₂N)₂CHOt-Bu (3 equivalents). After 24hours, the solvent was evaporated and the crude product 3 was utilizedwithout purification. ¹H NMR (CDCl₃) δ 4.4 (s, 2H), 4.8 (s, NH), 6.8-7.4(m, 13H).

Example 4

4-(4-phenyl-1H-pyrazole-3-yl)-1H-pyrrole-2-carboxylic acid benzylamide(II-5): To a solution of compound 3 (1 equivalent) in ethanol, atambient temperature, was added hydrazine hydrate (3 equivalents) and theresulting mixture heated at reflux. After 12 hours, the solvent wasevaporated and the crude product purified by preparatory HPLC (reversephase; 10→90% MeCN in water; 15 minutes) to afford the desired compoundII-5. LC/MS (M+1) 343.3, (M−1) 341.2.

Example 5

We have prepared other compounds of formula II by methods substantiallysimilar to those described in the above Examples 1-4 and thoseillustrated in Scheme I. The characterization data for these compoundsis summarized in Table 3 below and includes LC/MS, HPLC, and ¹H NMRdata.

For compounds where the HPLC Method is designated as “A”, the followingmethod was utilized: a gradient of water:MeCN, 0.1% TFA (95:5→0:100) wasrun over 22 minutes at 1 mL/min and 214 nm. For compounds where the HPLCMethod is designated as “B”, the following method was utilized: agradient of water:MeCN, 0.1% TFA (90:10→0:100) was run over 8 minutes at1 mL/min and 214 nm. Each of methods A and B utilize the YMC ODS-AQ 55120A column with a size of 3.0×150 mm. The term “T_(ret)(min)” refers tothe retention time, in minutes, associated with the compound using thedesignated HPLC method.

Where applicable, ¹H NMR data is also summarized in Table 3 belowwherein “Y” designates ¹H NMR data is available and was found to beconsistant with structure. Compound numbers correspond to the compoundnumbers listed in Table 1.

TABLE 3 Characterization Data for Selected Compounds Compound No M + 1 M− 1 HPLC Method T_(ret) (min) ¹H NMR II-41 407.4 405.4 A 8.6 Y II-42560.2 558.1 A 9.5 — II-43 — — A 10.5 — II-44 530.3 528.2 A 6.3 — II-45 —— A 9.8 — II-46 — — A 10.6 — II-50 377.4 — A 10.1 Y II-52 530.2 528.2 A10.3 — II-53 378.4 376.3 A 7.4 Y II-56 490.2 488.1 A 10.8 — II-58 — — A10.46 — II-59 — — A 9.1 — II-63 361.4 359.3 A 9.5 Y II-65 — — A 10.0 —II-67 378.4 376.3 A 7.4 Y II-72 451.5 449.1 A 10.15 Y II-80 374.4 372.3A 6.6 — II-83 435.3 433.4 A 10.3 — II-85 — — A 10.6 — II-86 — — A 9.3 —II-88 380.4 378.3 A 6.9 — II-89 — — A 10.5 — II-91 — — A 9.6 — II-92377.4 375.3 A 10.2 Y II-94 — — A 9.0 — II-97 342.1 — B 3.8 Y II-98 380.4378.3 A 6.7 — II-102 — — A 10.3 — II-103 — — A 10.6 — II-105 — — A 9.3 —II-109 — — A 7.9 — II-110 — — A 10.3 — II-111 361.4 359.3 A 9.4 Y II-113— — A 10.6 — II-116 380.2 378.4 A 6.9 — II-117 373.4 — A 9.0 Y II-119362.4 371.4 A 6.5 — II-120 373.4 371.4 A 8.2 — II-122 — — A 10.8 —II-123 — — A 11.4 — II-126 — — A 10.2 — II-128 — — A 10.9 — II-130 — — A7.4 — II-133 — — A 9.5 — II-134 306.1 — B 3.5 Y II-135 353.4 351.4 A 7.7— II-137 313.3 311.2 A 6.4 Y II-141 380.4 378.3 A 6.7 — II-143 280.1 — B3.3 Y II-144 336.4 — B 3.5 — II-145 373.4 — B 2.8 — II-146 — — A 10.5 —II-147 362.4 — B 3.5 — II-148 327.3 325.2 A 9.2 Y II-149 332.4 — B 3.5 —II-150 322.4 — B 3.2 — II-151 316.2 314.2 A 10.3 Y II-152 — — A 6.6 —II-153 323.4 — B 2.3 — II-154 343.4 — B 2.8 — II-158 294.3 — B 3.4 —II-159 335.4 — B 2.7 — II-161 389.3 387.2 A 8.9 — II-162 300.3 298.2 A9.5 Y II-163 366.5 364.4 B 6.0 — II-164 297.3 — A 5.1 Y II-165 322.3325.2 A 9.7 Y II-167 316.2 314.2 A 10.0 Y II-168 312.3 310.2 A 8.6 YII-169 281.1 — B 3.9 Y II-170 312.3 310.2 A 9.1 Y II-171 300.3 298.2 A9.4 Y II-172 297.3 295.7 A 5.5 Y II-174 449.3 447.2 A 12.5 Y II-175477.3 475.3 A 14.0 Y II-176 374.4 372.4 A 6.3 — II-178 362.4 360.0 A 6.6— II-179 374.4 372.4 A 6.3 — II-180 404.4 402.4 A 6.4 — II-181 380.2378.3 A 6.7 — II-182 355.4 353.4 A 7.7 — II-183 367.4 365.4 A 7.4 —II-184 355.4 353.4 A 7.9 — II-185 367.4 365.3 A 7.5 — II-186 397.4 395.4A 7.1 — II-187 373.4 371.4 A 8.0 — II-188 373.4 371.4 A 7.9 — II-189382.4 380.4 A 6.9 — II-190 394.4 392.4 A 6.7 — II-191 382.4 380.4 A 7.0— II-192 394.5 392.4 A 6.7 — II-193 424.4 422.4 A 6.4 — II-194 400.4398.4 A 7.3 — II-195 400.4 398.4 A 7.1 — II-196 400.4 398.4 A 7.2 —II-197 341.3 339.2 A 7.5 — II-198 353.4 351.4 A 7.1 — II-199 341.3 339.2A 7.6 — II-200 383.4 381.4 A 6.9 — II-201 359.4 357.4 A 8.0 — II-202359.4 357.4 A 7.8 — II-203 359.4 357.4 A 7.7 — II-204 354.4 352.4 A 6.2— II-205 366.4 364.4 A 5.9 — II-206 354.4 .52.4 A 5.6 — II-207 396.4394.4 A 5.9 — II-208 372.4 370.4 A 6.7 — II-209 372.4 370.4 A 6.5 —II-210 372.4 370.4 A 6.4 — II-237 — — A 9.8 — II-238 — — A 11.6 — II-239— — A 11.3 — II-240 — — A 7.5 — II-241 — — A 12.0 — II-242 — — A 11.7 —II-243 — — A 11.6 — II-244 389.4 387.3 A 10.2 — II-245 — — A 10.6 —II-246 365.4 363.4 A 7.5 — II-247 — — A 7.2 — II-248 — — A 8.0 — II-249— — A 7.7 — II-267 — — A 10.7 — II-268 — — A 10.0 — II-269 — — A 12.2 —II-270 — — A 12.3 — II-271 — — A 9.3 — II-272 — — A 12.7 — II-273 — — A12.7 — II-274 — — A 3.8 — II-275 — — A 10.3 — II-276 — — A 8.4 — II-277— — A 10.6 — II-278 — — A 12.8 — II-279 — — A 11.4 — II-280 — — A 7.9 —II-281 — — A 11.5 — II-282 — — A 8.6 — II-283 — — A 8.4 — II-284 — — A12.2 — II-290 — — A 11.4 — II-291 — — A 9.7 — II-292 — — A 9.1 — II-293481.3 479.3 A 8.3 — II-294 455.4 453.3 A 6.9 — II-295 — — A 7.5 — II-296— — A 8.9 — II-298 353.4 — B 2.8 — II-299 421.3 423.2 A 10.1 —

Example 6

ERK Inhibition Assay:

Compounds were assayed for the inhibition of ERK2 by aspectrophotometric coupled-enzyme assay (Fox et al (1998) Protein Sci 7,2249). In this assay, a fixed concentration of activated ERK2 (10 nM)was incubated with various concentrations of the compound in DMSO (2.5%)for 10 min. at 30° C. in 0.1 M HEPES buffer, pH 7.5, containing 10 mMMgCl₂, 2.5 mM phosphoenolpyruvate, 200 μM NADH, 150 μg/mL pyruvatekinase, 50 μg/mL lactate dehydrogenase, and 200 μM erktide peptide. Thereaction was initiated by the addition of 65 μM ATP. The rate ofdecrease of absorbance at 340 nM was monitored. The IC₅₀ was evaluatedfrom the rate data as a function of inhibitor concentration.

Table 4 shows the results of the activity of selected compounds of thisinvention in the ERK2 inhibition assay. The compound numbers correspondto the compound numbers in Table 1. Compounds having an activitydesignated as “A” provided a K_(i) value below 1 micromolar; compoundshaving an activity designated as “B” provided a K_(i) value between 1and 5 micromolar; and compounds having an activity designated as “C”provided a K_(i) value greater than 5 micromolar.

TABLE 4 ERK2 Inhibitory Activity of Selected Compounds No. Activity No.Activity No. Activity II-1 A II-2 C II-3 A II-4 A II-5 A II-6 A II-7 CII-8 C II-9 C II-10 C II-11 C II-12 C II-13 A II-14 C II-16 C II-17 CII-18 A II-19 A II-20 A II-21 C II-22 A II-23 A II-24 A II-25 C II-26 AII-27 A II-28 A II-29 C II-30 A II-31 C II-39 A II-40 A II-41 A II-42 AII-43 A II-44 A II-45 A II-46 A II-47 A II-48 A II-49 A II-50 A II-51 AII-52 A II-53 A II-54 A II-55 A II-56 A II-57 A II-58 A II-59 A II-60 AII-61 A II-62 A II-63 A II-64 A II-65 A II-66 A II-67 A II-68 A II-69 AII-70 A II-71 A II-72 A II-73 A II-74 A II-75 A II-76 A II-77 A II-78 AII-79 A II-80 A II-81 A II-82 A II-83 A II-84 A II-85 A II-86 A II-87 AII-88 A II-89 A II-90 A II-91 A II-92 A II-93 A II-94 A II-95 A II-96 AII-97 A II-98 A II-99 A II-100 A II-101 A II-102 A II-103 A II-104 AII-105 A II-106 A II-107 A II-108 A II-109 A II-110 A II-114 A II-115 AII-116 B II-117 B II-118 B II-119 B II-120 B II-121 B II-122 B II-123 BII-124 B II-125 B II-126 B II-127 B II-128 B II-129 B II-130 B II-131 BII-132 B II-133 B II-134 B II-135 B II-136 B II-137 B II-138 B II-139 BII-140 B II-141 B II-142 B II-143 B II-144 B II-145 B II-146 B II-147 BII-148 B II-149 B II-150 B II-151 B II-152 B II-153 B II-154 B II-155 BII-156 B II-157 B II-158 B II-159 B II-160 B II-161 C II-162 C II-163 CII-164 C II-165 C II-166 C II-167 C II-168 C II-169 C II-170 C II-171 CII-172 C II-285 B II-286 C II-287 C II-288 B II-289 C II-290 B II-291 CII-292 C II-293 C II-294 C II-295 C II-296 C II-297 C II-298 C II-299 C

Example 7

ERK Inhibition Cell Proliferation Assay:

Compounds were assayed for the inhibition of ERK2 by a cellproliferation assay. In this assay, a complete media was prepared byadding 10% fetal bovine serum and penicillin/streptomycin solution toRPMI 1640 medium (JRH Biosciences). Colon cancer cells (HT-29 cell line)were added to each of 84 wells of a 96 well plate at a seeding densityof 10,000 cells/well/150 μL. The cells were allowed to attach to theplate by incubating at 37° C. for 2 hours. A solution of test compoundwas prepared in complete media by serial dilution to obtain thefollowing concentrations: 20 μM, 6.7 μM, 2.2 μM, 0.74 μM, 0.25 μM, and0.08 μM. The test compound solution (50 μL) was added to each of 72cell-containing wells. To the 12 remaining cell-containing wells, onlycomplete media (200 μL) was added to form a control group in order tomeasure maximal proliferation. To the remaining 12 empty wells, completemedia was added to form a vehicle control group in order to measurebackground. The plates were incubated at 37° C. for 3 days. A stocksolution of ³H-thymidine (1 mCi/mL, New England Nuclear, Boston, Mass.)was diluted to 20 μCi/mL in RPMI medium then 20 μL of this solution wasadded to each well. The plates were further incubated at 37° C. for 8hours then harvested and analyzed for ³H-thymidine uptake using a liquidscintillation counter.

Selected compounds of this invention that inhibit ERK in the colon cellproliferation assay, with an IC₅₀ of less than 10 μM include: II-43,II-48, and II-45.

Example 8

JAK Inhibition Assay:

Compound inhibition of JAK may be assayed by the method described by G.R. Brown, et al, Bioorg. Med. Chem. Lett. 2000, vol. 10, pp 575-579 inthe following manner. Into Maxisorb plates, previously coated at 4° C.with Poly (Glu, Ala, Tyr) 6:3:1 then washed with phosphate bufferedsaline 0.05% and Tween (PBST), is added 2 μM ATP, 5 mM MgCl₂, and asolution of compound in DMSO. The reaction is started with JAK enzymeand the plates incubated for 60 minutes at 30° C. The plates are thenwashed with PBST, 100 μL HRP—Conjugated 4G10 antibody is added, and theplate incubated for 90 minutes at 30° C. The plate is again washed withPBST, 100 μL TMB solution is added, then the plates are incubated foranother 30 minutes at 30° C. Sulfuric acid (100 μL of 1M) is added tostop the reaction and the plate is read at 450 nM to obtain the opticaldensities for analysis to determine IC₅₀ values.

Example 9

JNK Inhibition Assay:

Compounds were screened in the following manner for their ability toinhibit JNK using a spectrophotometric coupled-enzyme assay. To an assaystock buffer solution containing 0.1 M HEPES buffer (pH 7.5), 10 mMMgCl₂, 2.5 mM phosphoenolpyruvate, 200 μM NADH, 150 μg/mL pyruvatekinase, 50 μg/mL lactate dehydrogenase, and 200 μM EGF receptor peptide(with sequence KRELVEPLTPSGEAPNQALLR), were added various concentrationsof the compound in DMSO and a fixed concentration (10 nM) of activatedJNK. The resulting mixture was incubated at 30° C. for 10 minutes thenthe reaction was initiated by the addition of 10 μM ATP. The decrease ofabsorbance at 340 nM at 30° C. was monitored as a function of time andthe resulting data was fitted to a competitive inhibition kinetic modelto determine the K_(i).

Table 5 shows the results of the activity of selected compounds of thisinvention in the JNK inhibition assay. The compound numbers correspondto the compound numbers in Table 1. Compounds having an activitydesignated as “A” provided a K_(i) value below 1 micromolar; compoundshaving an activity designated as “B” provided a K_(i) value between 1and 5 micromolar; and compounds having an activity designated as “C”provided a K_(i) value greater than 5 micromolar.

TABLE 5 JNK Inhibitory Activity of Selected Compounds No. Activity No.Activity II-39 B II-48 A II-40 A II-51 B II-43 A II-55 A II-46 A II-104B II-47 B II-112 C

Example 10

Aurora Inhibition Assay:

Compounds were screened in the following manner for their ability toinhibit Aurora using a standard coupled enzyme assay. To an assay stockbuffer solution containing 0.1M HEPES 7.5, 10 mM MgCl₂, 25 mM NaCl, 2.5mM phosphoenolpyruvate, 300 μM NADH, 30 μg/mL pyruvate kinase, 10 μg/mLlactate dehydrogenase, 40 μM ATP, and 800 μM peptide (LRRASLG, AmericanPeptide, Sunnyvale, Calif.) was added a 30 μM solution of the compoundin DMS0 and the resulting mixture incubated at 30° C. for 10 min. Thereaction was initiated by the addition of 10 μL of 70 nM Aurora and 1 mMDTT. The rates of reaction were obtained by monitoring absorbance at 340nM over a 5 minute read time at 30° C. using a BioRad Ultramark platereader (Hercules, Calif.). The IC₅₀ was determined from the rate data asa function of inhibitor concentration.

Table 6 shows the results of the activity of selected compounds of thisinvention in the Aurora2 inhibition assay. The compound numberscorrespond to the compound numbers in Table 1. Compounds having anactivity designated as “A” provided an IC₅₀ value below 5 micromolar;compounds having an activity designated as “B” provided an IC₅₀ valuebetween 5 and 10 micromolar; and compounds having an activity designatedas “C” provided an IC₅₀ value greater than 10 micromolar.

TABLE 6 Aurora2 Inhibitory Activity of Selected Compounds No. ActivityNo. Activity No. Activity II-48 A II-89 A II-211 B II-51 B II-93 AII-212 B II-54 B II-98 B II-213 B II-57 A II-99 A II-214 B II-61 AII-101 A II-215 B II-64 A II-103 B II-216 B II-66 B II-106 B II-218 BII-70 B II-108 B II-228 A II-72 B II-112 A II-252 B II-76 A II-113 AII-254 A II-77 A II-114 A II-255 B II-80 C II-115 A II-258 C II-81 AII-141 A II-259 B II-82 A II-142 A II-260 C II-85 B II-181 B II-262 BII-88 B II-188 C II-266 B

Example 11

GSK-3 Inhibition Assay:

Compounds were screened in the following manner for their ability toinhibit Glycogen Synthase Kinase 3 (GSK-3) using a standard coupledenzyme assay (Fox et al (1998) Protein Sci 7, 2249). To an assay stockbuffer solution containing 0.1M HEPES 7.5, 10 mM MgCl₂, 25 mM NaCl, 2.5mM phosphoenolpyruvate, 300 μM NADH, 1 mM DTT, 30 μg/mL pyruvate kinase,10 μg/mL lactate dehydrogenase, 300 μM peptide (HSSPHQp-SEDEEE, AmericanPeptide, Sunnyvale, Calif.), and 60 nM GSK-3, was added a 30 μM solutionof the compound in DMSO and the resulting mixture incubated at 30° C.for 5 min. The reaction was initiated by the addition of 10 μM ATP. Therates of reaction were obtained by monitoring absorbance at 340 nM overa 5 minute read time at 30° C. using a Molecular Devices plate reader(Sunnyvale, Calif.). The IC₅₀ was determined from the rate data as afunction of inhibitor concentration.

Table 7 shows the results of the activity of selected compounds of thisinvention in the GSK-3 inhibition assay. The compound numbers correspondto the compound numbers in Table 1. Compounds having an activitydesignated as “A” provided an IC₅₀ value below 10 micromolar; compoundshaving an activity designated as “B” provided an IC₅₀ value between 10and 20 micromolar; and compounds having an activity designated as “C”provided an IC₅₀ value greater than 20 micromolar.

TABLE 7 GSK-3 Inhibitory Activity of Selected Compounds No. Activity No.Activity No. Activity II-89 C II-115 C II-263 A II-93 C II-127 B II-271A II-94 C II-199 C II-278 A II-99 A II-214 C — — II-108 B II-227 B — —

Example 12

KDR Inhibition Assay:

Compounds were screened for their ability to inhibit KDR using astandard coupled enzyme assay (Fox et al., Protein Sci., (1998) 7,2249). Assays were carried out in a mixture of 200 mM HEPES 7.5, 10 mMMgCl2, 25 mM NaCl , 1 mM DTT and 1.5% DMSO. Final substrateconcentrations in the assay were 300 μM ATP (Sigma Chemicals) and 10 μMpoly E4Y (Sigma). Assays were carried out at 37° C. and 30 nM KDR. Finalconcentrations of the components of the coupled enzyme system were 2.5mM phosphoenolpyruvate, 200 μM NADH, 30 μg/ML pyruvate kinase and 10μg/ml lactate dehydrogenase.

An assay stock buffer solution was prepared containing all of thereagents listed above, with the exception of ATP and the test compoundof interest. 177 μl of the stock solution was placed in a 96 well platefollowed by addition of 3 μl of 2 mM DMSO stock containing the testcompound (final compound concentration 30 μM). The plate waspreincubated for about 10 minutes at 37° C. and the reaction initiatedby addition of 20 μl of ATP (final concentration 300 μM). Rates ofreaction were obtained using a Molecular Devices plate reader(Sunnyvale, Calif.) over a 5 minute read time at 37° C. Compoundsshowing greater than 50% inhibition versus standard wells containing theassay mixture and DMSO without test compound were titrated to determineIC₅₀ values.

Selected compounds of this invention that inhibit KDR at 2 μMconcentration in the above assay, with a percent inhibition of greaterthan 40%, include: II-43, II-48, II-304, and II-305.

Example 13

AKT Inhibition Assay:

Compounds were screened for their ability to inhibit AKT using astandard coupled enzyme assay (Fox et al., Protein Sci., (1998) 7,2249). Assays were carried out in a mixture of 100 mM HEPES 7.5, 10 mMMgCl2, 25 mM NaCl , 1 mM DTT and 1.5% DMSO. Final substrateconcentrations in the assay were 170 μM ATP (Sigma Chemicals) and 200 μMpeptide (RPRAATF, American Peptide, Sunnyvale, Calif.). Assays werecarried out at 30° C. and 45 nM AKT. Final concentrations of thecomponents of the coupled enzyme system were 2.5 mM phosphoenolpyruvate,300 μM NADH, 30 μg/ML pyruvate kinase and 10 μg/ml lactatedehydrogenase.

An assay stock buffer solution was prepared containing all of thereagents listed above, with the exception of AKT, DTT, and the testcompound of interest. 56 μl of the stock solution was placed in a 384well plate followed by addition of 1 μl of 2 mM DMSO stock containingthe test compound (final compound concentration 30 μM). The plate waspreincubated for about 10 minutes at 30° C. and the reaction initiatedby addition of 10 μl of enzyme (final concentration 45 nM) and 1 mM DTT.Rates of reaction were obtained using a BioRad Ultramark plate reader(Hercules, Calif.) over a 5 minute read time at 30° C. Compounds showinggreater than 50% inhibition versus standard wells containing the assaymixture and DMSO without test compound were titrated to determine IC₅₀values.

Selected compounds of this invention that inhibit AKT include: II-89,II-94, and II-305.

While we have described a number of embodiments of this invention, it isapparent that our basic examples may be altered to provide otherembodiments which utilize the compounds and methods of this invention.Therefore, it will be appreciated that the scope of this invention is tobe defined by the appended claims rather than by the specificembodiments which have been represented by way of example.

We claim:
 1. A compound of formula I:

or a pharmaceutically acceptable derivative or prodrug thereof, wherein;R¹ is selected from R, halogen, N(R⁸)₂, OR, NRCOR, NRCON(R⁸)₂, CON(R⁸)₂,SO₂R, NRSO₂R, or SO₂N(R⁸)₂; T is selected from a valtence bond or alinker group selected from: —O—, —S—, —NH₂—, or an optionallysubstituted C₁₋₆ alkylidene chain wherein up to two saturated carbons ofthe chain are optionally replaced by —C(═O)—, —CONH—, CONHNH—, —CO₂—,—NHCO₂—, —O—, —NHCONH—, —OC(═O)—, —OC(═O)NH—, —NHNH—, —NHCO—, —O—, —S—,—SO—, —SO₂—, —NH—, —SO₂NH—, or NHSO₂—; each R is independently selectedfrom hydrogen or an optionally substituted aliphatic group having one tosix carbons; R² is selected from hydrogen, CN, halogen, aryl, aralkyl,heteroaryl, heterocyclyl, an optionally substituted acyclic aliphaticchain group having one to six carbons, or an optionally substitutedcyclic aliphatic group having four to ten carbons; R³ is selected fromR, OH, OR, N(R⁸)₂, halogen, or CN; Q is J; J is —C(═O)—; R⁴ is —NHR⁵; R⁵—(CH₂)_(y)CH(R⁶) (R⁷); y is 0-6; R⁶ is an optionally substituted groupselected from an aryl, aralkyl, aralkoxy, heteroaryl, heteroarylalkyl,heteroarylalkoxy, heterocyclyl, heterocyclylalkyl, orheterocyclylalkoxy, group; R⁷ is independently selected from anoptionally substituted aliphatic, hydroxyalkyl, alkoxyalkyl,aryloxyalkyl, or alkoxycarbonyl; each R⁸ is independently selected fromR, or two R⁸ on the same nitrogen taken together with the nitrogenoptionally form a four to eight membered, saturated or unsaturatedheterocyclic ring having one to three heteroatoms; and eachsubstitutable ring nitrogen is optionally substituted by R, NR₂, COR,CO₂(C₁-C₆ optionally substituted alkyl), SO₂ (C₁-C₆ optionallysubstituted alkyl) , CONR₂, and SO₂NR₂.
 2. The compound according toclaim 1 having the formula

or a pharmaceutically acceptable derivative or prodrug thereof.
 3. Thecompound according to claim 2 having one or more of the followingfeatures: (a) T is a valence bond; (b) R¹ is hydrogen or NHR; (c) R² isan optionally substituted aryl ring; and (d) R³ is hydrogen.
 4. Thecompound according to claim 1 wherein said compound is selected from thefollowing Table 1 compounds: TABLE 1 Compounds II II

No. T-R² Q-R⁴ II-39  3,5-Cl₂-phenyl

II-41  5-Cl-phenyl CONH(2-OH-1-Ph-ethyl) II-42  4-OH,3-I,5-nitrophenylCONH(2-OH-1-Ph-ethyl) II-44  3-NH₂, 4-OH, 5-I-phenylCONH(2-OH-1-Ph-ethyl) II-49  5-CF₃-phenyl CONH(2-OH-1-Ph-ethyl) II-59 5-Br-phenyl

II-62  5-Br-phenyl CONH(1-Ph-propyl) II-72  5-Br-phenylCONH(2-OH-1-Ph-ethyl) II-75  5-Me-phenyl CONH(2-OH-1-Ph-ethyl) II-86 5-Br-phenyl CONH(3-OH-1-Ph-propyl) II-91  5-Br-phenyl

II-174 5-Cl-phenyl

II-175 5-Cl-phenyl

II-293 5-Br-phenyl

II-294 5-Br-phenyl

II-296 5-Br-phenyl

II-300 3-Cl-phenyl

II-301 3-Cl-phenyI

II-302 3-Cl-phenyl

II-303 3-Cl-phenyl

II-304 3-Cl-phenyl

II-305 3-Cl-phenyl

II-306 3-Cl-phenyl

II-307 3-Cl-phenyl

II-308 3-Cl-phenyl

II-309 3-Cl-phenyl

II-310 3,5-Cl₂-phenyl

II-311 3-Br-5-CF₃-phenyl

II-312 3-Cl-phenyl

II-313 3,5-Cl₂-phenyl

II-314 3-Cl-4-CN-phenyl

II-315 3-Cl-4-CH₂OH-phenyl

II-316 3-Cl-4-CH₂NH₂-phenyl

II-317

II-318

II-319

II-320

II-321

II-322


5. The compound according to claim 1 having the formula:

or a pharmaceutically acceptable derivative or prodrug thereof.
 6. Thecompound according to claim 5 wherein: T is a valence bond; and R² is anoptionally substituted aryl ring.
 7. The compound according to claim 1wherein said compound is selected from the following Table 2 compounds:TABLE 2 Compounds II-B II-B

No. R T-R² Q-R⁴ II-B-23 H 3-Cl-phenyl

II-B-24 H 3-Cl-phenyl

II-B-25 Me 3,5-Cl₂-phenyl

II-B-26 H


8. A composition comprising a compound according to any one of claims1-3 or 6-9 in an amount sufficient to detectably inhibit protein kinesehactivity, said protein kinase selected from one or more of ERK, JAK,JNK, Aurora, GSK, KDR, ART, or a protein kinase related thereto; and apharmaceutically acceptable carrier.
 9. The composition according toclaim 8 wherein said compound is formulated in a pharmaceuticallyacceptable manner for administration to a patient.
 10. A compositionaccording to claim 8 further comprising a therapeutic agent, either aspart of a multiple dosage form together with said compound or as aseparate dosage form.
 11. A method of inhibiting protein kinase activityin a biological sample, wherein said protein kinase is selected fromELK, JAK, JNK, Aurora, GSK, KDR, AKT, or a protein kinase relatedthereto, comprising the step of contacting said sample with a compoundaccording to any one of claims 1-3 or 6-9.
 12. A method for treating aprotein kinase-mediated disease state in a patient, wherein said proteinkinase is selected from one or more of ERK, JAK, JNK, Aurora, KDR, AKT,or a protein kinase related thereto, comprising the step ofadministering to said patient a composition according to claim
 11. 13.The method according to claim 12, comprising the additional step ofadministering to said patient a therapeutic agent either as part of amultiple dosage form together with said compound or as a separate dosageform.
 14. A method of treating a disease state in a patient, whereinsaid disease state is selected from cancer, stroke, diabetes,hepatomegaly, cardiovascular disease, Alzheimer's disease, cysticfibrosis, viral disease, autoimmune diseases, atherosclerosis,restenosis, psoriasis, allergic disorders, inflammation, neurologicaldisorders, a hormone-related disease, conditions associated with organtransplantation, immunodeficiency disorders, destructive bone disorders,proliferative disorders, infectious diseases, conditions associated withcell death, thrombin-induced platelet aggregation, chronic myelogenousleukemia (CML), liver disease, pathologic immune conditions involving Tcell activation, or CNS disorders, comprising the step of administeringto said patient a composition according to claim
 10. 15. The methodaccording to claim 14 wherein the disease state is cancer.
 16. Themethod according to claim 15 wherein the disease state is a cancerselected from breast; ovary; cervix; prostate; testis, genitourinarytract; esophagus; larynx, glioblastoma; neuroblastoma; stomach; skin,keratoacanthoma; lung, epidermoid carcinoma, large cell carcinoma, smallcell carcinoma, lung adenocarcinoma; bone; colon, adenoma; pancreas,adenocarcinoma; thyroid, follicular carcinoma, undifferentiatedcarcinoma, papillary carcinoma; seminoma; melanoma; sarcoma; bladdercarcinoma; liver carcinoma and biliary passages; kidney carcinoma;myeloid disorders; lymphoid disorders, Hodgkin's, hairy cells; buccalcavity and pharynx (oral), lip, tongue, mouth, pharynx; small intestine;colon-rectum, large intestine, rectum; brain and central nervous system;or leukemnia.
 17. The method according to claim 15 comprising theadditional step of administering to said patient a chemotherapeuticagent either as part of a multiple dosage form together with saidcompound or as a separate dosage form.
 18. The method according to claim14 wherein the disease state is cardiovascular disease.
 19. The methodaccording to claim 18 wherein the disease state is a cardiovasculardisease selected from restenosis, cardiomegaly, artherosclerosis,myocardial infarction, or congestive heart failure.
 20. The methodaccording to of claim 18 comprising the additional step of administeringto said patient a therapeutic agent for treating cardiovascular diseaseeither as part of a multiple dosage form together with said compound oras a separate dosage form.
 21. A composition for coating an implantabledevice comprising a compound according to claim 1 and a carrier suitablefor coating said implantable device.